The recognition of several monogenic diseases which can present with ND has led to an improved understanding of the possible mechanisms of polygenic non-mendelian inherited ND. These monogenic syndromes include CAPS (Cryopyrin-Associated Periodic Syndromes), DIRA [Deficiency of IL-1 receptor antagonist (IL-1RA)], DITRA [Deficiency of IL-36 receptor antagonist (IL-36RA)], PAPA (Pyogenic sterile arthritis, PG, and acne), and chronic recurrent multifocal osteomyelitis (CRMO) (21, 22).

CAPS are a group of rare inherited inflammatory disorders associated with dominant mutations in the cryopyrin-coding gene NLRP3 (nucleotide-binding domain, leucine-rich repeat containing gene family, pyrin domain-containing protein 3) on chromosome 1q44 which is also known as CIAS1, PYPAF1, or NALP3. Currently, more than 90 mutations involving NLRP3 and associated with CAPS phenotypes have been reported.

CAPS contain a spectrum of hereditary periodic fever syndromes including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells Syndrome (MWS), and chronic infantile neurological cutaneous and articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID). Characteristic symptoms are periodic fever and urticarial lesions. Dependent on severity, they can be associated with several clinical manifestations, including arthritis, conjunctivitis, amyloidosis, sensorineural hearing loss, aseptic meningitis, and/or cerebral atrophy (17).

DIRA is an autosomal recessive mutation in IL1RN (IL-1RA gene) on chromosome 2 leading to the absence of IL-1RA, resulting in an IL-1 signaling hyperactivity (13, 23). DIRA manifest as perinatal-onset pustular dermatitis, joint swelling, painful osteolytic lesions, and periostitis.

DITRA is caused by homozygous or compound heterozygous damaging mutations in IL36RN and is characterized by generalized pustular rashes and systemic inflammation (14, 15). IL36RN encodes for IL-36RA which inhibits binding of IL-36 to its receptor. When IL36RA is functionally impaired there is an enhanced IL-36R signaling which directly and indirectly attracts immune cells, especially neutrophils, giving rise to the pustular rashes (14, 15). IL-36 has been reported to be upregulated in a psoriasis-like inflammatory mouse model (24), confirming the role of this cytokine family in the pathogenesis of pustular psoriasis (25). Moreover, a strong correlation has been demonstrated in human psoriatic skin between the expression of IL-36 and that of other cytokines, such as IL-17, IL-23, TNF-α, and IFN-γ (26), suggesting that a positive gene expression loop might occur in psoriasis. Moreover, IL-36 also enhances IL-1α levels, further amplifying the inflammatory network (27). Thus, the IL-1/IL-36 inflammatory axis appears to be a key player of disease pathology in generalized pustular psoriasis (28) and its role may be intriguingly hypothesized also in other NDs, although it needs to be confirmed by dedicated studies.

PAPA syndrome is due to two primary mutations (A230T and E250Q) in the gene encoding proline–serine–threonine phosphatase interactive protein 1 (PSTPIP1) (10, 29). Hyperphosphorylation of the mutated PSTPIP1 protein results in increased pyrin mediated activation of the inflammasome, dysregulation of caspase 1, and overexpression of IL-1β (29). The presence of a prototypical ND such as PG in the context of PAPA syndrome, caused by a single inflammasome regulator gene mutation, suggests an autoinflammatory component in the pathophysiology of NDs (30). The occurrence of mutations in a single gene encoding an inflammasome regulating protein, as seen in PAPA, is similar to what happens in the first monogenic autoinflammatory conditions identified, i.e., familial Mediterranean fever and CAPS. Yet further studies have identified autoinflammatory syndromes with features of ND that are linked to mutations in multiple genes. In addition to PAPA, PG can present with other autoinflammatory syndromes including PG, acne, and suppurative hidradenitis (PASH) and pyogenic arthritis, PG, acne, and suppurative hidradenitis (PAPASH). The findings of these syndromic forms of PG along with reports of familial presentations of PG suggest the shared genetic basis of this ND (1, 11, 12, 31, 32).

Investigation of 7 cases of PASH and 13 cases of isolated PG revealed multiple mutations in a variety of autoinflammatory genes, including PSTPIP1, Mediterranean fever (MEFV), Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), NLRP3, NLRP12, Lipin 2 (LPIN2) (2). The MEFV gene encodes for the protein pyrin, which is an innate immune system sensor which plays a central role in inflammasome activation. Different mutations in the genetic sequence can lead to variable clinical presentations with overlapping features.

In NDs, MEFV (S242R) mutations have been identified and lead to a chronically active pathogen-related response with inflammasome activation and IL-1β secretion (33). NOD2 is an intracellular pattern recognition receptors (PRRs) that plays a key role in orchestrating the proper assembly of autophagy-related proteins. Autophagy involves a cellular response resulting in the degradation of cytoplasmic components and is important in the transfer of microbial components to intracellular PRRs. The catabolic autophagy pathway responds to a wide variety of cellular stressors including nutrient deprivation, hypoxia, DNA damage, mechanical injury, reactive oxygen species (ROS), and the presence of microbial ligands (34). Loss of function mutations in NOD2 result in impaired autophagy and have been associated with inflammatory bowel disease (IBD), a condition characterized by heightened production of proinflammatory cytokines and often associated with ND comorbidity (35). Autophagy has been shown to be important in mitochondrial homeostasis (36) and its deficiency is associated with increased mitochondrial membrane permeability and ROS production, and the release of mitochondrial DNA into the cytosol (36–38). Mitochondrial DNA and ROS are both activators of the NLRP3 inflammasome (36, 37). Studies have revealed that macrophages with defective autophagy have decreased NLRP3 inflammasome activation (38). We speculate that mutations in NOD2 lead to defective autophagy causing increased production of ROS and the release of mitochondrial DNA resulting in NLRP3 activation and subsequent ND. These findings point to the polygenic basis of NDs and helped establish the categorization of NDs among the autoinflammatory disorders. The polygenic nature suggests that NDs arise from a multifactorial response in genetically predisposed patients.

In normal physiology, neutrophils are heralded as major effector cells in acute inflammation. As the most abundant leukocytes in circulation, neutrophils have been extensively described as protagonists against infection and innate immune system responders to insults. Within the bone marrow, the production and differentiation of neutrophils is regulated primarily by granulocyte colony-stimulating factor (G-CSF) (39). G-CSF also acts to promote release of mature neutrophils from the bone marrow into circulation. This is accomplished by the uncoupling of the CXC-chemokine receptor 4 (CXCR4) and CXC-chemokine ligand 12 (CXCL12) (39).

Within tissues, the “neutrostat” loop is a feedback pathway which normally suppresses neutrophilic response by suppressing production of G-CSF. This loop is initiated after phagocytosis of infiltrative neutrophils, resulting in suppression of IL-23 production by resident macrophages and dendritic cells and subsequent decreased secretion of IL-17, an important promoter of G-CSF production (40–42). Evaluation of patients with NDs has shown significantly elevated serum G-CSF, and therapeutic G-CSF is implicated in a majority of drug-induced SS cases, indicating a plausible but undiscovered contributing mechanism underlying ND (43–47). In addition, elevated IL-17 levels have been found in tissue samples from patients with PG, SS, and APF, a rare ND presenting with pustular lesions typically involving the skin folds and anogenital area (48–52). IL-17 is a key cytokine in both activation and induction of neutrophils to produce IL-8, a potent chemokine that is the principle chemoattractant of neutrophils. Increased levels of IL-8 have been found in ND lesional skin, and the chemokine works synergistically with TNF-α to potentiate and maintain a proinflammatory state (1, 2, 16, 18–21, 49, 50, 53). In mice models, experiments have revealed that protein kinase C α (PKCα) within keratinocytes promotes neutrophil infiltration of the epidermis, and may also play a central role in upregulation of G-CSF and IL-6 gene expression independent of TNF-α signaling, giving the possibility of a peripheral mechanism of ND (54).

The innate immune system uses germline encoded PRRs to recognize pathogen-associated molecular patterns (PAMPs), including (foreign) PAMPs and (endogenous) damage-associated molecular patterns (DAMPs), to initiate the production of proinflammatory cytokines (55). Changes in local cellular homeostasis including temperature, pH, oxygen, and osmolarity are recognized as DAMPs by resident tissue macrophages (55). Recognition of DAMPs initiates an inflammatory cascade involving the inflammasome which consists of a central scaffold of proteins, a sensor (including Nod-like Receptors), the adaptor protein ASC [apoptosis associated speck-like protein containing a caspase-associated recruitment domain (CARD)] and the effector protein caspase-1 (22). Members of the NLRP (Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain-containing) family, are the primary cytoplasmic PRRs that mediate inflammasome activation (55). Oligomerization of the inflammasome results in caspase-1 activation leading to the cleavage of pro-IL-1β and pro-IL-18 to IL-1β and IL-18 (22, 55). Gain-of-function mutations in NLRP3 gene are responsible for the development of autosomal dominant inflammatory disorders which typically presents with episodic urticarial neutrophil-rich cutaneous lesions, known as CAPS (see above) (56). Although NLRP3 mutations are prototypically responsible for inflammasome activation, other mutations such as those involving IL-1 and IL-36 pathway genes may also induce inflammasome activation (13, 14). The symptoms of CAPS are the result of overexpression of IL-1β secondary to constitutive activation of the cytoplasmic macromolecular complex. Evaluation of patients with ND have also shown elevated serum and lesional tissues IL-β levels (50, 57, 58). In addition, keratinocytes exposed to ultraviolet B irradiation, contact allergens or in the setting of psoriasis activate similar inflammasome pathways resulting in IL-1β production and subsequent neutrophil localization and activation (59–61), although there is support from mouse models that bone marrow-derived cells with isolated NLRP3 mutations are sufficient to induce IL-1β associated cutaneous autoinflammation (62).

Immune cell proinflammatory signal transduction is inhibited by the tyrosine phosphatase known as Src homology region 2 (SH2) domain–containing phosphatase-1 (SHP-1) (63, 64). Dysfunctional activity of SHP-1 is associated with various diseases including multiple sclerosis, leukemia and psoriatic arthritis (65–69). SHP-1, also known as PTPN6 (protein tyrosine phosphatase nonreceptor type 6), is encoded by the gene Ptpn6. Heterozygous mutations and splice variants of Ptpn6 have been identified in patients with PG and SS (4).

Ptpn6^spin mice are the product of a Y208N (or Tyr208Asn) missense mutation leading to amino acid substitution in the carboxy-terminal SH2 domain of SHP-1. These mice develop severe cutaneous inflammation driven by overexpression of IL-1α (6). Histopathologically, the inflammatory cutaneous lesions resemble human NDs, with neutrophil-rich infiltrate and pustules within the epidermis, and are associated with neutrophilia. These data may support the role of mutations involving Ptpn6 in triggering NDs in humans.

The Kanneganti group have utilized this murine model to characterize key regulatory components of neutrophil-mediated cutaneous autoinflammation. These authors have surprisingly shown that IL-1α signaling, but not IL-1β or caspase-1 associated inflammasome, plays a key role in orchestrating cutaneous autoinflammation in Ptpn6^spin mice (6). Their work has elucidated the complex regulation of the IL-1α pathway and identified a number of signaling components as pivotal in the development of cutaneous inflammation in Ptpn6^spin mice, such as IL-1 receptor (IL-1R), myeloid differentiation primary response gene 88 (MyD88) (7), spleen tyrosine kinase (Syk) (7), receptor interacting protein kinase 1 (RIPK1) (6), tumor growth factor-β activated kinase 1 (TAK1) (7) and apoptosis signal-regulating kinase 1 (ASK1) (8).

SHP-1 was also shown to regulate IL-1α signaling primarily through preventing phosphorylation of MyD88 by Syk (7). This pathway is illustrated in Figure 1. Of note, the Kanneganti group showed that inflammation in Ptpn6^spin mice is independent of toll-like receptors (TLRs), IFN-α/β receptor (IFNAR), integrin β-3 (ITGB3), NOD2–RIPK2 signaling, and independent of stimulator of IFN genes (STING) (7, 70). Support for unique role of IL-1α signaling in the development of cutaneous inflammation in Ptpn6^spin mice is strengthened by ruling out the influence of these additional innate immune signaling pathways (7, 70).

Recently, CARD9 signal transduction was identified as an essential mediator of cutaneous inflammation in Ptpn6^spin mice (71).

CARD9 is an adapter protein downstream of Syk and is central transducer for multiple innate signaling pathways including the C type lectin receptors, Dectin-1 and Mincle pathways (72). CARD9 forms a complex with MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) and BCL10 (B-cell lymphoma/leukemia 10) leading to initiation of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling cascade and increased transcription of pro-inflammatory cytokines (TNF and IL-6) resulting in T helper (Th)17 polarization (73).

As previously discussed, IL-17 is a key signaling molecule in ND pathogenesis. CARD9 is thus linked to cytokine production, innate anti-fungal immunity, and myeloid cell activation (72). Identification of the key role of CARD9 in the autoinflammatory signaling pathway suggests the interconnection between NDs and other autoinflammatory conditions. Interestingly, CARD9 mutations are associated with IBD (74) and deletion in CARD9 significantly dampens the IL1-mediated cutaneous inflammatory disease in a mouse model knockout for CARD9 (70). Aberrant signaling involving SHP-1, Syk, and CARD9 can lead to neutrophil-mediated autoinflammation driven by overproduction of IL-1α. Thus, blocking these signals may provide a novel approach to design effective therapeutic strategies to treat NDs.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.